Adequate nutrition depends on the integrity of the gastrointestinal (Gl) motor apparatus. When a primary Gl motility disorder is present, such as gastroparesis and chronic idiopathic pseudo-obstruction, it is often accompanied by the inability to maintain appropriate weight. In conditions where the primary defect is not a motility disease but rather a chronic or chronic intermittent caloric deficit arising e.g. from lack of food, impaired calorie utilization or abnormal eating behaviors, impaired Gl motor function including delayed gastric emptying and dyspeptic symptoms is often seen. Thus, regardless of etiology, Gl dysmotilities may occur in any disorder and condition associated with chronic or chronic intermittent negative energy balance. It follows that the caloric deficit that occurs in severe Gl motor disorders may further aggravate the primary Gl dysmotilities and contribute to the therapeutic challenge they represent, while the dysmotilities associated with non-GI causes of calorie deficit may make refeeding more difficult. Our overall goal is to identify the cellular mechanisms whereby caloric deficit interferes with normal Gl motor functions. Our specific aims are to investigate whether (i) gastric dysmotility in caloric restriction develops from dystrophy of key cell types of the tunica muscularis such as smooth muscle cells, interstitial cells of Cajal and enteric neurons; and whether (ii) these changes are mediated by reduced systemic and local production of insulin-like growth factor-l (IGF-1), a key trophic factor; and by a loss of protection by heme oxygenase 1 (H01) from oxidative stress, which is increased in intermittent food restriction. We will use mouse models of chronic and chronic intermittent caloric restriction with or without treatments to elevate IGF-1 and HOI levels. We will also examine gastric tissues from patients suffering from severe weight loss and in normal controls. We will utilize state-of-the-art in vivo techniques (gastric emptying breath test, small animal MRI and PET) and in vitro approaches (flow cytometry, confocal microscopy, electrophysiology, real-time RT-PCR, Western blotting) to assess gastric function and central responses and to study the tissue-, cellular, and molecular mechanisms of dysmotilities. Results from this project may provide novel adjuvant therapeutic approaches to reversing loss of key cell types causing abnormal motor function.